The project is based on preliminary data showing an age-related quantitative decline in fracture healing in a[unreadable] murine model, with reproducible findings of delayed chondrogenesis and subsequent chondrocyte[unreadable] hypertrophy. In addition vascularization and remodeling of the mineralized cartilage is diminished. In[unreadable] conjunction with this, a decline in smurf2 expression in fracture callus occurs with aging, as well as a decline[unreadable] in COX-2 expression. Given the known effect of smurf2 on enhancing chondrocyte maturation and[unreadable] mineralization, and preliminary data indicating stimulation of smurf2 expression by PTH, the effects of PTH[unreadable] on restoring smurf2 expression and enhancing healing of fractures in aging mice will be evaluated.[unreadable] Determination of the role of the target cells of the periosteum will also be investigated using allografting with[unreadable] periosteal cells from genetically marked donor mice. The Specific Aims are:[unreadable] 1. Comprehensive quantitative characterization of fracture healing in young and aging mice using[unreadable] histomorphometry, microCT, and biomechanical analysis will be correlated with gene expression, with focus[unreadable] on TGF-beta/BMP and PTH/PTHrP signaling pathways.[unreadable] 2. Determining the differences in the capacity of periosteal stem cells from young and old mice to[unreadable] initiate bone repair and the roles of COX2 and PTHrP. The reparative potential of periosteum in young and[unreadable] old mice will be evaluated to determine if tissue from young animals can restore fracture healing in aged[unreadable] mice. Based on known loss of COX-2 with aging and impaired healing in Cox-2 -/- mice, effects of[unreadable] periosteum from COX-2 -/- and COX-2 +/- on healing in young and old mice will be evaluated. Finally,[unreadable] periosteum from coHAIPTHR transgenic mice will be evaluated in aging mice to determine if PTH/PTHrP[unreadable] signal pathway activation can restore healing in COX-2 -/- or aging mice. Healing will be evaluated by[unreadable] microCT, histomorphometry, and biomechanical testing in all cases.[unreadable] 3. Defining the effect of PTH during the various stages of fracture repair in aged mice.[unreadable] Despite data and clinical use of PTH in fracture healing stimulation, there is not a clear understanding of[unreadable] the mechanisms involved or stage of the repair process affected by PTH. The ability to improve fracture[unreadable] repair in aged mice, and ability of PTH to compensate for the loss of Cox-2 will be evaluated. Effects on[unreadable] smurfl and 2 expression during fracture healing, about which little is currently known, will also be[unreadable] investigated.